PROJECT SUMMARY/ABSTRACT Dr. Kristina Burrack?s research has led to the identification of a cytokine complex treatment that stimulates natural killer (NK) cells to produce the immunosuppressive cytokine IL-10 and prevents mice from dying from an immune-mediated disease following Plasmodium infection known as cerebral malaria. Malaria is a significant global health problem with more than 200 million clinical cases and nearly 500,000 deaths annually. Cerebral malaria (CM) is a deadly complication of Plasmodium infection that mostly afflicts children under the age of five and can result in long-term neurologic deficits in children who survive. In the human disease and the mouse model of cerebral malaria, a pathologic immune response is thought to contribute to disruption of the blood brain barrier. In the present proposal, Dr. Burrack will more fully elucidate the role of cytokine complex-stimulated NK cells in cerebral malaria and the induction of IL-10 in human and mouse NK cells. In addition to direct support from mentors and collaborators, Dr. Burrack has full access to the shared resources in the Center for Immunology at the University of Minnesota, including core facilities in flow cytometry, animal facilities, and biostatistics. Interactions with collaborators at the University of Minnesota, Hennepin Healthcare Research Institute, the Mayo Clinic, and elsewhere will allow her to gain further expertise in the analysis of molecular signaling pathways, analyze human NK cells, generate new mouse strains, and further investigate the cerebral malaria mouse model, which will be critical as she transitions into the independent phase of her career. The data generated from the proposed studies will form the basis for an R01 application. The proposed studies are significant because they address a critical gap in basic research that is needed to fully characterize NK cell activation following cytokine stimulation ? specifically, how to induce IL-10-producing suppressive NK cells ? and understand the mechanisms that prevent fatal immunopathology. These findings will have major clinical implications for the design of adjunctive therapies for human cerebral malaria and other immunopathologic diseases and inform the development of novel NK cell-directed therapies. Dr. Burrack?s long-term goal is to dedicate her career to advancing basic and translational immunology and infectious disease research as an independent investigator at an academic institution. As an immunologist with a deep interest and proven track record in studying the pathogenesis of infectious diseases of global health importance, she is in a unique position to answer the questions set forth in this proposal and to rapidly advance the understanding of how to tune NK cell stimulation to prevent immunopathology and the role of IL-10- producing NK cells in the pathogenesis of cerebral malaria.